Abstract
Cerebellar Purkinje cells (PCs) are sensitive to ethanol, but the effect of ethanol on spontaneous complex spike (CS) activity in these cells in vivo is currently unknown. Here, we investigated the effect of ethanol on spontaneous CS activity in PCs in urethane-anesthetized mice using in vivo patch-clamp recordings and pharmacological manipulation. Ethanol (300 mM) induced a decrease in the CS-evoked pause in simple spike (SS) firing and in the amplitude of the afterhyperpolarization (AHP) under current clamp conditions. Under voltage-clamp conditions, ethanol significantly decreased the area under the curve (AUC) and the number of CS spikelets, without changing the spontaneous frequency of the CSs or the instantaneous frequency of the CS spikelets. Ethanol-induced a decrease in the AUC of spontaneous CSs was concentration dependent. The EC50 of ethanol for decreasing the AUC of spontaneous CSs was 168.5 mM. Blocking N-methyl-D-aspartate receptors (NMDARs) failed to prevent the ethanol-induced decreases in the CS waveform parameters. However, blockade of cannabinoid receptor 1 (CB1) significantly suppressed the ethanol-induced effects on the CS-evoked pause in SS firing, amplitude of the AHP, spikelet number and the AUC of CSs. Moreover, a CB1 receptor agonist not only reduced the number of spikelets and the AUC of CSs, but also prevented the ethanol-induced inhibition of CS activity. Our results indicate that ethanol inhibits CS activity via activation of the CB1 receptor in vivo in mice, suggesting that excessive ethanol intake inhibits climbing fiber (CF)–PC synaptic transmission by modulating CB1 receptors in the cerebellar cortex.
Highlights
The cerebellum integrates sensory and motor information and generates motor-related outputs that are involved in motor coordination, motor learning and the fine adjustment of voluntary movement
Ethanol (300 mM) did not change the frequency of spontaneous complex spike (CS) activity (Figures 2A,B) or the instantaneous frequency of CS spikelets (Figures 2A,D), but it decreased the number of spikelets and the area under the curve (AUC) of CS-evoked inward currents to 73.4 ± 6.8% of baseline (ACSF: 100.1 ± 4.9%, n = 8 cells, P = 0.016; Figures 2A,C) and 69.1 ± 7.5% of baseline (ACSF: 100.0 ± 5.1%, n = 8 cells, P = 0.008; Figures 2A,E), respectively
We demonstrated that ethanol dose-dependently depresses spontaneous CS activity in Purkinje cells (PCs)—the alcohol decreased the AUC, the number of spikelets and the amplitude of the AHP
Summary
The cerebellum integrates sensory and motor information and generates motor-related outputs that are involved in motor coordination, motor learning and the fine adjustment of voluntary movement. Cerebellar Purkinje cells (PCs) receive sensory and motor information through the mossy fiber–parallel fiber (MF–PF) and the climbing fiber (CF) pathways (Ito, 1984). The CFs make synapses with PC dendrites that excite PCs by generating powerful excitatory postsynaptic potentials (EPSPs), called complex spikes (CSs; Simpson et al, 1996; Strata and Rossi, 1998). Activation of the CF evokes a strong and irregular all-or-none CS that consists of a fast sodium spike and several spikelets (Ito, 1984). CF discharges modulate the frequency and pattern of PC simple spike (SS) output by punctuating tonic activity with variable-duration pauses (Ebner et al, 1983; Barmack and Yakhnitsa, 2003; Cerminara and Rawson, 2004)
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